platforms R Kaplan MRC Clinical Trials Unit at UCL R Kaplan - - PowerPoint PPT Presentation

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Single arm trials in the context (era) of platforms

R Kaplan MRC Clinical Trials Unit at UCL

R Kaplan

NCI-MATCH trial

NCI-MATCH Expanding to 24 Arms in Late May 2016

Arm / Target Drugs(s) A EGFR mut Afatinib B HER2 mut Afatinib C1 MET amp Crizotinib* C2 MET ex 14 sk Crizotinib* E EGFR T790M AZD9291 F ALK transloc Crizotinib G ROS1 transloc Crizotinib H BRAF V600

Dabrafenib+trametinib

I PIK3CA mut Taselisib N PTEN mut GSK2636771 P PTEN loss GSK2636771 Q HER 2 amp Ado-trastuzumab emtansine Arm / Target Drug(s) R BRAF nonV600 Trametinib S1 NF1 mut Trametinib S2 GNAQ/GNA11 Trametinib T SMO/PTCH1 Vismodegib U NF2 loss Defactinib V cKIT mut Sunitinib W FGFR1/2/3 AZD 4547* X DDR2 mut Dasatinib Y AKT1 mut AZD 5363* Z1A NRAS mut Binimetinib* Z1B CCND1,2,3 amp Palbociclib* Z1D dMMR Nivolumab* *Pending approval

R Kaplan

Lung MATRIX trial

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Lung Map trial

mCRC First line chemo 16 wks Stable/ responding

REGISTER

Biomarker analysis during 1st 8-12 wks

RANDOMISE

Novel agent

P CAP

No Rx

ALLOCATE

BRAF mut PIK3CA mut All WT Non-strat

Diagnostic biopsy

Restart first line chemo on progression Primary endpoint: PFS in the interval rebiopsy rebiopsy A N D B

MSI/MMR def Synthetic lethality cohort

E

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

C

R Kaplan

How useful is Objective Response?

• May help in dose/schedule selection
• Objective response remains a useful early

readout that is helpful to developers and exciting to patients, media and investors

• RECIST complexity, pseudoprogression . . .
• Waterfall plots reveal some responses in control

arms, even placebo arms, of some RCTs

• Objective responses to combinations are a

minefield

• Proof of benefit almost always requires

associated solid TTE (or duration) endpoints

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Drawbacks of single arm design

• Implicit comparison with historical data may no

longer be valid in the stratified medicine era

• Impact of pre-Rx parameters usually greater than

the impact of the treatment

• May be able to minimise by extensive

characterisation, including of historical controls

• For many agents, and settings, OR or duration is not

going to be all that’s needed

• May provide a ‘Go’ but perhaps not a reliable ‘No-go’

R Kaplan

Drawbacks of single arm design

• Biomarker enrichment may not be definitive
• Can’t separate prognostic from predictive effects

0% 10% 20% 30% 40% 50% 60%

Marker present Marker absent

Std Exp Treatment Clinical Endpoint <- Worse Better ->

Std Exp

Treatment Clinical Endpoint <- Worse Better ->

Prognostic biomarker

Std Exp

Treatment Clinical Endpoint <- Worse Better -> Std Exp Treatment Clinical Endpoint <- Worse Better ->

Predictive biomarker Prognostic and predictive

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Dan Sargent’s group: modelling

• Variability in historical control success rates, outcome

drifts in patient populations over time, and/or patient selection effects can result in inaccurate false-positive and false-negative error rates in single-arm designs

• False-positive error rates (type I error) 2-4 times higher

than in randomised phase II trials

• Increasing sample size did not correct the over-optimism
• f single-arm studies

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Other problems with SATs

• Association of ORR with overall survival

questionable at best

• Combinations still hold more promise than single

drugs

• ORR limited to neoadjuvant and end-stage
• Apparently good results can make subsequent

randomised trial more difficult

• May be time-inefficient except in genuinely rare

tumour subsets

mCRC First line chemo 16 wks Stable/ responding

REGISTER

Biomarker analysis during 1st 8-12 wks

RANDOMISE

Novel agent

P CAP

No Rx

ALLOCATE

BRAF mut PIK3CA mut All WT Non-strat

Diagnostic biopsy

Restart first line chemo on progression Primary endpoint: PFS in the interval rebiopsy rebiopsy A N D B

MSI/MMR def Synthetic lethality cohort

E

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

Novel agent

P

C

R Kaplan

One FOCUS4 cohort

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Single-arm Ph II vs Randomised Ph II

Single-arm Phase II for ORR:

• 27 patients (25 evaluable) recruited over 3 mos
• + 16 wks (4 mos) for full assessment of response
• + 1 mo for data checking and analysis
• Time elapsed = 7 months
• If encouraging:
• + 6 mos to set up a randomised phase II
• Sub-total: time to start of ph II = 13 months (minimum)
• Total: 24-30 mos until ph II completed

Randomised (2:1) Phase II for PFS + ORR:

• At 9 mos: 24 pts on active arm evaluable for ORR; plus stage 1 PFS

analysis available (81 pts randomised)

• At 16 mos: final randomised phase II PFS analysis available

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Other arguments for randomised Ph II

• Randomised phase II may provide ‘No-go’ decisions

almost as quickly as single arm

• ‘Go’ decisions become ‘Go-on’, with the next needed

dataset already well underway

• No disadvantage if the response data are so dramatic

that ready to approach regulators

• Provides a much fuller toxicity/safety profile
• plus PD, plus data for Health Economics/HTA assessment
• possibly plus useful translational, biomarker data, etc.
• The more that durable responses are critical, the better

the argument for randomising & seamless ph 2/3 design

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Comments / Questions?